Summary/Abstract During brain development, after initial circuit formation, neuronal arbors are further refined by experience during a period of activity-dependent plasticity. This use-dependent selection of appropriate connections, leads to retention of some branches while others are eliminated, and is critical for generating efficient functional circuits. It is thought that many neurodevelopmental disorders, including ones that effect visual perception, result from disruption of experience-dependent plasticity leading to deficits in synaptic connectivity, stabilization, or maturation. Unfortunately, little is known about the molecular mechanisms regulating selective synapse and dendrite stabilization in response to activity. In the previous grant periods we showed that cpg15, discovered in a screen for activity-regulated genes, is regulated by light-driven neural activity in the visual system, and that the CPG15 protein promotes dendritic and axonal arbor growth, and enhances synaptic maturation. We propose investigating the cpg15 KO mouse towards the goal of understanding in molecular detail the mechanisms that underlie activity-dependent plasticity. Based on preliminary data we hypothesize that CPG15 acts to stabilize nascent synapses on dendritic spines resulting in spine and arbor stabilization and synaptic maturation. When CPG15 is expressed in response to activity, it provides a saliency signal for selective stabilization of active synapses. We propose combining molecular genetics with electrophysiology, visual manipulations, in vivo two-photon microscopy, and optical imaging of intrinsic signal, to test the hypothesis that CPG15 is required and sufficient for experience- dependent stabilization of synaptic and neuronal structures and that its function is critical for experience- dependent developmental plasticity. Our studies focus on the visual cortex, where anatomical and physiological studies provide a rich and well-characterized experimental toolkit for manipulating experience, and where our previous work has shown that spatio-temporal cpg15 expression coincides with developmental sites and times of activity-dependent circuit wiring.